The overall objective of this project is to provide a more detailed description of neuroanatomical and neurochemical systems underlying depressed behavior. These studies will use rats, and the data obtained will be compared to results of PET studies in depressed patients, using the same tracer kinetic measurements of glucose metabolism, cerebral blood flow, and ligand binding. The animal studies will also provide insight into the functional mechanisms underlying observed changes in these systems. These insights will be important for the construction of future human studies and for the development of new therapies for depressed patients. Two hypotheses will be studied. First, that a specific set of limbic structures are involved in mediating depressed behaviors. Second, that catecholamines and serotonin are concurrently involved in the same behaviors. These experiments are designed to study glucose metabolism, using 14-C-2 deoxyglucose (2DG) quantitative autoradiography. Our experiments will also study local cerebral blood flow, using 14-C-iodoantipyrine (IAP) quantitative autoradiography. These techniques will be used in four rat models of human depressed behavior. Reversals of metabolic, blood flow, and behavioral changes occurring during depressed conditions will be investigated using two representative antidepressant drugs. The first will be a tricyclic (imipramine); the second will be a MAO inhibitor, tranylcypromine. Mechanisms underlying these observed changes will then be studied using self-stimulation and lesion techniques. Finally, in vitro receptor binding studies, using tritium-labeled ligands and contact autoradiography will examine changes in serotonin-2, alpha-2 and beta adrenergic, and dopamine receptors during depressed conditions.